Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes.

OBJECTIVE: To determine the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes.

RESEARCH DESIGN AND METHODS: A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose Ra , Rd , and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate <15 mmol/L, venous pH <7.35, or capillary ketones >5.0 mmol/L.

RESULTS: At baseline, glucose Ra was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose Rd area under the curve (AUC)0-180 min and β-hydroxybutyrate (BOHB) AUC0-180 min were significantly higher. There was a small but significantly higher glycerol Ra (measure of lipolysis) AUC0-180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and <27 kg/m2 , basal glucose Ra , BOHB, and glycerol Ra AUC0-180 min were significantly higher in the low-BMI group with dapagliflozin treatment versus the low-BMI group with placebo.

CONCLUSIONS: During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role.